Sensory signs in complex regional pain syndrome and peripheral nerve injury.

This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%-69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%-31%) and dynamic mechanical allodynia (24%-28%) were less frequent than heat or pressure hyperalgesia (36%-44%, 67%-73%), and mechanical hypoesthesia (31%-55%) was more frequent than thermal hypoesthesia (30%-44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research.

Association between wind-up ratio and central serotonergic function in healthy subjects and depressed patients.

Temporal summation of C-fiber evoked responses generates an increase in action potential discharge in second-order neurons and in perceived pain intensity (wind-up). This may be related to the central serotonergic system which modulates and partly inhibits sensory input. Aim of the study was to investigate the relationship between wind-up and serotonergic activity using loudness dependence of auditory evoked potentials (LDAEP). 18 healthy subjects were compared to 18 patients with major depression, a disease with a putative serotonin deficit. They were examined with quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain (DFNS), including the wind-up ratio (WUR), LDAEP, and psychometric measurements. We found a slight positive correlation between WUR and LDAEP both in healthy controls and depressed patients combined (r=0.340, p=0.043), indicating that WUR may be modulated by serotonergic activity. It can be concluded that inhibitory control to noxious stimuli is partly associated with the central serotonergic function as indicated by LDAEP.

A modified score to identify and discriminate neuropathic pain: a study on the German version of the Neuropathic Pain Symptom Inventory (NPSI).

BACKGROUND: Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain. METHODS: We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles. RESULTS: Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct. CONCLUSIONS: The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain.

Pain-associated mild sensory deficits without hyperalgesia in chronic non-neuropathic pain.

OBJECTIVES: A mixture of sensory loss and gain is a hallmark of neuropathic pain. But hypesthesia and hyperalgesia also occur with experimentally induced acute pain. Here, we assessed sensory profiles in chronic non-neuropathic pain (osteoarthritis, OA) using the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain (DFNS). METHODS: Twenty individuals with OA [mean pain intensity on the numerical rating scale (NRS, 0-10): 5.6±1.5] were tested on the painful and contralateral hand and compared with 20 healthy volunteers matched for age, sex, and handedness. RESULTS: In the OA group, analysis of variance revealed increased detection thresholds to tactile stimuli bilaterally and to thermal stimuli restricted to the more painful hand (all P<0.05). Pin-prick hypoalgesia was present restricted to the patients' more affected hand. Neither hyperalgesia nor allodynia was found. QST parameters were correlated with average pain intensity (r between 0.48 and 0.51). CONCLUSIONS: These results suggest that chronic non-neuropathic pain may induce slight sensory impairment for large fiber function (bilateral) and small fiber function (ipsilateral). However, all changes are within the normal range, in contrast to patients with neuropathy. Inhibition of central pathways by nociceptive input and altered sensory processing due to disuse of the hand are possible mechanisms. These functional sensory alterations do not interfere with the diagnosis of neuropathy.

Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.

The quality of pain management in German hospitals.

BACKGROUND: The Pain-Free Hospital Project was initiated in 2003 with the aim of improving pain management throughout Germany. We assessed the current state of pain management in German hospitals. METHODS: From 2004 to 2006, data were obtained anonymously from 2252 patients who had undergone surgery, and 999 who had been treated non-surgically, in a total of 25 hospitals. They were interviewed about the intensity of pain they had experienced and about the effectiveness of its treatment. RESULTS: No pain at all was reported by 12.4% of patients who had undergone surgery and by 16.7% of the non-surgically treated patients. Moderate to severe pain at rest was reported by 29.5% of the surgical group and 36.8% of the non-surgical group. More than 50% of the overall group reported pain on movement. 55% of the surgical group, and 57% of the non-surgical group, were dissatisfied with their pain management. Peak pain tended to occur outside normal working hours. No analgesic treatment at all was given to 39% of patients in the non-surgical group, even though they were in pain; the corresponding figure for the surgical group was 15% (a significant difference, p<0.001). Inadequately effective pain management was reported by 45.6% of patients in the non-surgical group and 29.6% in the operative group (again, a significant difference. Cancer patients were treated more often with potent opioids. CONCLUSION: Severe postoperative pain is still too common among hospitalized patients, particularly pain that is induced by movement. Patients being treated on non-surgical wards also often suffer severe pain needlessly. Pain management seems to be worse for non-surgical patients (cancer patients excepted) than for surgical patients: waiting times for medication are longer, and ineffective medications are given more often. On the other hand, a number of hospitals provide positive examples of the potential effectiveness of pain management for both surgical and non-surgical patients.

A simplified screening protocol predicts pathological electroneurographic results in patients with suspected polyneuropathy.

Electroneurographic testing is one of the standard instruments to detect polyneuropathy (PNP). The objective of this study was to develop a screening tool with optimized sensitivity and specificity, consisting of a short questionnaire and a short standardized neurological examination. One hundred one patients with a suspected PNP were prospectively selected from the neurological outpatient clinic. We used a short questionnaire and a short neurological examination derived from the Michigan Neuropathy Screening Instrument (MNSI). Based on electroneurographic results, patients were classified in three groups of different severity. The diagnostic power of the MNSI was optimized by constructing a score based on two combined discrimination functions. The optimized screening tool was able to detect patients suffering from PNP at a sensitivity of 88%. In particular, a severe form of PNP was recognized at a sensitivity of 97%. The specificity to detect healthy subjects was 74%. This new tool is a fast and easy to use instrument which can give a decision support for general practitioners for patients with a suspected PNP as to whether a subsequent electroneurographical examination (ENG) testing will show pathological results.

Sensory changes and loss of intraepidermal nerve fibers in painful unilateral nerve injury.

OBJECTIVES: Dysaesthesias is a common symptom in patients with neuropathic pain after peripheral nerve injury (PNI). In contrast to neuropathies with comparable symptoms there is little knowledge of the underlying mechanisms in PNI patients. METHODS: Quantitative sensory testing according to the German Research Network on Neuropathic Pain protocol, and changes in intraepidermal nerve fiber density were assessed in 15 patients with dysaesthesias after PNI of the lower limb. According to their small-fiber function patients were assigned into 2 subgroups. RESULTS: The sensory profiles of PNI patients were characterized predominantly by minus symptoms (significantly increased thresholds for perception of cold, warm, touch and vibration, and significantly increased thresholds for heat and mechanical pain) on the affected compared with the unaffected side. The only plus symptom reported was a significantly reduced pressure pain threshold. The sensory profile of patients with a severe loss of small-fiber function (n=7) showed a thermal and tactile hypoaesthesia and hypoalgesia; this was in contrast to patients with a moderate loss of small-fiber function, who showed a mild thermal and tactile hypoaesthesia associated with an increased mechanical pain sensitivity. Mean intraepidermal nerve fiber density was significantly decreased in the affected compared with unaffected skin [3.50 (4.00) vs. 11.10 (7.60) fibers/mm] and correlated with warm and mechanical detection thresholds (both r=-0.60). DISCUSSION: In conclusion, even though patients presented with comparable clinical symptoms, their sensory profiles differed, supporting the concept of different underlying mechanisms leading to chronic pain in PNI patients. Skin biopsies support the validity of quantitative sensory testing.

Significant difference between three observers in the assessment of intraepidermal nerve fiber density in skin biopsy.

BACKGROUND: The determination of Intraepidermal Nerve Fiber Density (IENFD) in skin biopsy is a useful method for the evaluation of different types of peripheral neuropathies. To allow a reliable use of the method it is necessary to determine interobserver reliability. Previous studies dealing with this topic used limited suitable statistical methods. METHODS: In the present study three observers determined the IENFD and estimated the staining quality of the basement membrane for an adequate quantity of 120 skin biopsies (stained with indirect immunofluorescence technique) from 68 patients. More adequate statistical methods like intraclass correlation coefficient and Bland Altman Plot were chosen to estimate interobserver reliability. RESULTS: We found an unexpected significant difference in IENFD between the observers (p < 0.05) and so the results of this study are not in line with the high interobserver reliability reported before (intraclass correlation coefficient: 0.73). The Bland Altmann Plot showed a variance growing with rising mean. The difference in IENFD between the observers and the resulting low interobserver reliability is likely caused by different interpretations of the standard counting rules. There was no significant difference in IENFD between observers for biopsies with a well-defined basement membrane. Thus skin biopsies with an inexactly defined basement membrane should not be used diagnostically for the determination of IENFD. CONCLUSION: These results emphasise that standardisation of the method is extremely important and at least two observers should analyse skin biopsies with critical IENFD near the cut-off values.

Habituation and short-term repeatability of thermal testing in healthy human subjects and patients with chronic non-neuropathic pain.

We investigated habituation effects during thermal quantitative sensory testing (tQST) using 8 repetitive measurements for thermal detection and pain thresholds. The same measurements were repeated two days later. 39 healthy subjects and 36 patients with chronic non-neuropathic pain syndromes (migraine, tension-type headache, non-radicular back pain) were enrolled. The pain intensity was assessed using an 11-point (0-10) numerical rating scale. Measurements correlated significantly over the two days in both groups (r=0.41...0.62). Warm detection (WDT) and heat pain threshold (HPT) revealed no significant differences over these days. Cold detection (CDT) and pain thresholds (CPT) showed significant differences but these were small compared to the range of normal variability (CDTDelta -0.28 degrees C; CPTDelta 1.51 degrees C). On both days, WDT showed no habituation during measurements. Although there was a small difference in CDT and CPT between first and second measurement, there was no habituation beyond the second stimuli. In contrast, HPT significantly increased between first and sixth stimuli, indicating pronounced habituation. Average HPT of first to third measurement was significantly lower than HPT of the fourth to sixth assessment (45.9 degrees C; 47.7 degrees C) with a good day-to-day repeatability. Repeatability and habituation was identical in both groups. Ongoing pain intensity in the patient groups correlated significantly with CDT/WDT but not with CPT, HPT, indicating that ongoing pain might suppress the sensitivity to non-painful stimuli. In summary, tQST proved a reliable diagnostic tool for clinical practice. Day-to-day differences were small but without clinical relevance. Habituation was most pronounced for HPT, probably due to peripheral fatigue of the receptors.

Long-term skin temperature measurements - a practical diagnostic tool in complex regional pain syndrome.

Despite the development of the IASP criteria, diagnosing complex regional pain syndrome (CRPS) remains a challenge because all symptoms vary interindividually, including the vascular abnormalities. Previous studies showed that skin temperature asymmetries between the affected and contralateral extremity around 2 degrees C are useful for diagnosing CRPS. However, they were either assessed only at one single point in time or during specific investigations including controlled thermoregulatory modulation of sympathetic activity which limits their practicability. The present study evaluated long-term skin temperature changes under everyday circumstances in 22 patients with CRPS, 18 patients with limb pain of other origin and 23 healthy controls. The asymmetries in skin temperature and oscillation number (Q Oscill), the percentage of assessed time with a-synchron temperature changes on both body sides and the determination coefficient of the individual regression (r2 id) were compared between the groups. Patients with CRPS differed significantly from healthy controls in nearly all parameters. Minor differences between both patient groups were found regarding the percentage of assessed time with side difference >2 degrees C (DeltaT2). However, both patient groups differed significantly in parameters characterizing the skin temperature dynamics. A sum score (2 *Q Oscill +r2 id +DeltaT2) allowed diagnosing CRPS with a specificity of 67% vs. patients with other painful diseases and 79% vs. healthy controls (sensitivity: 73%, respectively, 94%) and reflected the severity of the dysfunction in CRPS better than the mean skin temperature side differences alone. The applied skin temperature analysis can be easily applied in the clinical settings and serves as a further facet in the difficult diagnosis of CRPS.

NeuroQuick--a novel bedside test for small fiber neuropathy?

BACKGROUND: An appropriate bedside test for small fiber neuropathy does not exist so far. Cold hypaesthesia occurs as an early onset symptom, and the new handheld device NeuroQuick (NQ) was recently claimed to be a valid and reliable screening tool for its quantitative assessment. AIMS: Comparison of the NQ with standardized quantitative sensory testing (QST) in patients suffering from chronic painful dysaesthesia with and without pathological cold detection threshold (CDT). METHODS: Forty-one patients with and without diabetes mellitus displaying chronic painful dysaesthesia were included (18 men, 55.8+/-13 years). According to the German network protocol QST was performed in the body area with the severest symptoms and at the opposite side as control after thorough clinical-neurological examination. The NeuroQuick, developed as quantitative bedside testing of cold thermal perception based on the wind chill, was used subsequently. RESULTS: DT was pathologically increased in 14 and within normal range in 27 patients; NQ values were pathological in 9 and non-pathological in 32 patients. Thus NQ obtained 7.4% false positive and 50% false negative results in detecting cold hypaesthesia, corresponding to 92.6% specificity, 50% sensitivity and a positive and negative predictive value of 78%, respectively. CONCLUSIONS: This study demonstrates that the NeuroQuick is not an adequate screening device for cold hypaesthesia in patients with chronic neuropathic pain. It exhibits a high specificity but only low sensitivity in the identification of such small fiber dysfunction; a reliable and valid screening tool should necessarily provide opposite features.